Eukaryotic cells contain a number of families of transcription factors which serve to rapidly induce expression of a variety of genes in response to extracellular stress or physiological signaling pathways. One important family of transcription factors mediating these responses is a factor named nuclear factor kappa B (NF-κB) and is composed of the NF-κB/Rel proteins. This factor, when in an active state, in turn activates genes involved in the mammalian body's response to inflammation, infection and stress. NF-κB is ubiquitously expressed but appears to play an important role in the etiology and progress of inflammatory disease, both chronic and acute, according to Barnes and Karin. NF-κB is rapidly activated by a wide variety of stimuli including cytokines, protein kinase C activators, viruses, ultraviolet radiation, immune stimuli and agents inducing oxidative stress leading to the production of reactive oxygen intermediates. It is believed that all of these act by means of specific protein kinases that degrade IκB whose biological role is to bind NF-κB and keep it in the inactive state in the cytoplasm. Antioxidants are also known to block the action of protein kinases indicating that reactive oxygen species may play an intermediary role. When IκB is phosphorylated, it is degraded by proteolytic reactions allowing the NF-κB to enter the nucleus and bind to DNA and transactivate target genes. The redox status of the cell appears to control the presence of IκB and therefore the activity of NF-κB. Antioxidants have been shown to inhibit the oxidative stress activation of NF-κB. Among the genes whose expression is increased by NF-κB are nitric oxide synthetase and cyclooxygenase-2, the latter being responsible for increased production of prostaglandins and thromboxane. NF-κB also regulates the expression of several genes that encode adhesion molecules which in turn recruit inflammatory cells.
Additionally, NF-κB plays a crucial role in the intracellular efficiency of gene expression and replication of the human immunodeficiency virus (HIV-1). Thus, inhibition of NF-κB could also play a role in the treatment of HIV-1 and other viral agents.
Finally, NF-κB status appears to play an important role in cancer treatment. For example, the discovery of Tumor Necrosis Factor (TNF) was hailed as a potential giant step in the treatment of cancer. It was found early on, however, that TNF did not kill most types of cancer cells. Apparently, TNF triggers one intracellular pathway that leads the cell to commit “suicide,” in a process called apoptosis, and simultaneously triggers another that activates a key molecule that blocks this pathway. This second pathway involved genes that were turned on by NF-κB which protected the cancer cells from TNF killing. Recently four separate groups have uncovered information that supports this hypothesis. First, Baltimore and co-workers discovered that mice lacking NF-κB die before birth, apparently from massive die-off of liver cells. This finding implied that NF-κB protects embryonic liver cells from committing suicide. Next, Sonenschein's group found that inhibiting NF-κB causes the B-cells of the immune system to die of apoptosis. These results were followed up by papers from the Baltimore group, from Verma's group at the Salk Institute and from Baldwin's group at University of North Carolina. Baltimore's group compared the effect of TNF on cells from treated mice lacking NF-κB and cells from normal mice. The cells from the normal mice survived but the cells from the mice lacking NF-κB died. Both other groups treated a variety of cells (tumor and non-tumor) with a mutant form a Ikb that acts to keep NF-κB irreversibly shackled in the cells cytoplasm. Cells treated with Ikb were all killed by TNF. It has been found that other oncolytic agents act on tumor cells in the same way as TNF; i.e., radiation and danorubicin. Therefore, the inhibition of NF-κB may enhance the anticancer activity of a number of chemotherapeutic agents that cause cell damage leading to cell suicide via the apoptotic process. Therefore we are providing a superior therapeutic process for NF-κB inhibition.